Growth hormone, which is secreted from the pituitary, stimulates growth of all tissues of the body that are capable of growing. In addition, growth hormone is known to have the following basic effects on the metabolic process of the body:
1. Increased rate of protein synthesis in all cells of the body; PA1 2. Decreased rate of carbohydrate utilization in cells of the body; PA1 3. Increased mobilization of free fatty acids and use of fatty acids for energy. PA1 q is 0 to 4; PA1 w is 0 or 1; PA1 X is C.dbd.O, O, S(O).sub.m, ##STR3## --CH.dbd.CH--; m is 0 to 2; ##STR4## is an R.sup.1, R.sup.2 independently disubstituted five- or six-membered heterocycle containing from one to three heteroatoms selected from nitrogen, oxygen or sulfur; where R.sup.1, R.sup.2 are as defined below; PA1 R.sup.7b CO(CH.sub.2).sub.v --, R.sup.7b O(CH.sub.2).sub.v CO--, R.sup.5b R.sup.12b N(CH.sub.2).sub.v --, PA1 R.sup.5b R.sup.12b NCO(CH.sub.2).sub.v --, R.sup.5b R.sup.12b NCS(CH.sub.2).sub.v --, PA1 R.sup.5b R.sup.12c NN(R.sup.12b)CO(CH.sub.2).sub.v --, PA1 R.sup.5b R.sup.12c NN(R.sup.12b)CS(CH.sub.2).sub.v --, PA1 R.sup.5b R.sup.12b NCON(R.sup.12a)(CH.sub.2).sub.v --, PA1 R.sup.5b R.sup.12b NCSN(R.sup.12a)(CH.sub.2).sub.v --, PA1 R.sup.5b R.sup.12c NN(R.sup.12b)CSN(R.sup.12a)(CH.sub.2).sub.v --, PA1 R.sup.5b R.sup.12c NN(R.sup.12b)CON(R.sup.12a)(CH.sub.2).sub.v --, PA1 R.sup.5b R.sup.12c NN(R.sup.12b)COO(CH.sub.2).sub.v --, R.sup.5b R.sup.12b NCOO(CH.sub.2).sub.v -- PA1 or R.sup.13 OCON(R.sup.12a)(CH.sub.2).sub.v --, where v is 0 to 3; PA1 n is 0 or 1; PA1 p is 0 to 3; PA1 q is 0 to 2; PA1 w is 0 or 1; PA1 X is O, S(O).sub.m, ##STR7## --CH.dbd.CH--; m is 0 to 2; PA1 R.sup.7b CO(CH.sub.2).sub.v --, R.sup.5b R.sup.12b N(CH.sub.2).sub.v --, PA1 R.sup.5b R.sup.12b NCO(CH.sub.2).sub.v --, R.sup.5b R.sup.12b NCS(CH.sub.2).sub.v --, PA1 R.sup.5b R.sup.12c NN(R.sup.12b)CO(CH.sub.2).sub.v --, PA1 R.sup.5b R.sup.12b NCON(R.sup.12a)(CH.sub.2).sub.v --, PA1 R.sup.5b R.sup.12b NCSN(R.sup.12a)(CH.sub.2).sub.v --, PA1 R.sup.5b R.sup.12c NN(R.sup.12b)CSN(R.sup.12a)(CH.sub.2).sub.v --, PA1 R.sup.5b R.sup.12c NN(R.sup.12b)CON(R.sup.12a)(CH.sub.2).sub.v --, PA1 R.sup.5b R.sup.12c NN(R.sup.12b)COO(CH.sub.2).sub.v --, R.sup.5b R.sup.12b NCOO(CH.sub.2).sub.v -- PA1 or R.sup.13 OCON(R.sup.12a)(CH.sub.2).sub.v --, and v is 0 to 3; PA1 n is 0 or 1; PA1 p is 0 to 2; PA1 q is 0 to 2; PA1 w is 0 or 1; PA1 X is S(O).sub.m or --CH.dbd.CH--; PA1 m is 0 or 1; PA1 R.sup.7b CO(CH.sub.2).sub.v --, R.sup.5b R.sup.12b N(CH.sub.2).sub.v --, PA1 R.sup.5b R.sup.12b NCO(CH.sub.2).sub.v --,R.sup.5b R.sup.12c NN(R.sup.12b)CO(CH.sub.2).sub.v --, PA1 R.sup.5b R.sup.12b NCON(R.sup.12a)(CH.sub.2).sub.v --, PA1 R.sup.5b R.sup.12c NN(R.sup.12b)CSN(R.sup.12a)(CH.sub.2).sub.v --, PA1 R.sup.5b R.sup.12c NN(R.sup.12b)CON(R.sup.12a)(CH.sub.2).sub.v --, PA1 R.sup.5b R.sup.12c NN(R.sup.12b)COO(CH.sub.2).sub.v --, R.sup.5b R.sup.12b NCOO(CH.sub.2).sub.v --, PA1 or R.sup.13 OCON(R.sup.12a)(CH.sub.2).sub.v --, where v is 0 to 2; PA1 n is 0 or 1; PA1 p is 0 to 2; PA1 q is 1; PA1 w is 1; PA1 X is S(O).sub.m or --CH.dbd.CH--; PA1 m is 0 or 1; PA1 R.sup.7b CO(CH.sub.2).sub.v --, R.sup.5b R.sup.12b N(CH.sub.2).sub.v --, PA1 R.sup.5b R.sup.12b NCO(CH.sub.2).sub.v --,R.sup.5b R.sup.12c NN(R.sup.12b)CO(CH.sub.2).sub.v --, PA1 R.sup.5b R.sup.12b NCON(R.sup.12a)(CH.sub.2).sub.v --, PA1 R.sup.5b R.sup.12c NN(R.sup.12b)CON(R.sup.12a)(CH.sub.2).sub.v --, PA1 R.sup.5b R.sup.12c NN(R.sup.12b)COO(CH.sub.2).sub.v --, R.sup.5b R.sup.12b NCOO(CH.sub.2).sub.v -- PA1 or R.sup.13 OCON(R.sup.12a)(CH.sub.2).sub.v --, where v is 0 to 2; PA1 1. 3-Amino-3-methyl-N-[6,7,8,9-tetrahydro-8-oxo-9-[[2'-(1H-tetrazol-5-yl)[1,1 '-biphenyl]-4-yl]methyl]-5H-pyrido[2,3-b]-azepin-7(R)-yl]butanamide; PA1 2. N-Ethyl-4'-[[7(R)-[[3-amino-3-methyl-1-oxobutyl]amino]-6,7,8,9-tetrahydro- 8-oxo-5H-pyrido[2,3-b]azepin-9-yl]-methyl][1,1'-biphenyl]-2-carboxamide; PA1 3. 3-Amino-3-methyl-N-[6,7,8,9-tetrahydro-8-oxo-9-[[2'-[[(methylamino)carbony l]amino][1,1'-biphenyl]-4-yl]-methyl]-5H-pyrido[2,3-b]azepin-7(R)-yl]butana mide; PA1 4. 3-Amino-3-methyl-N-[6,7,8,9-tetrahydro-8-oxo-9-[[2'-[[[(methylamino)carbon yl]amino]methyl][1,1'-biphenyl]-4-yl]methyl]-5H-pyrido[2,3-b]azepin-7(R)-yl ]butanamide; PA1 5. 3-Amino-N-[5,6,7,8-tetrahydro-5-oxo-4-[[2'-(1H-tetrazol-5-yl)[1,1'-bipheny l]-4-yl]methyl]-4H-thieno[3,2-b]azepin-6(R )-yl]-3-methylbutanamide PA1 6. N-Ethyl-4'-[[6(R)-[[3-amino-3-methyl-1-oxobutyl]amino]-5,6,7,8-tetrahydro- 5-oxo-4H-thieno[3,2-b]azepin-4-yl]-methyl][1,1'-biphenyl]-2-carboxamide; PA1 7. 3-Amino-N-[5,6,7,8-tetrahydro-5-oxo-4-[[2'-[[(methylamino)carbonyl]amino][ 1,1'-biphenyl]-4-yl]methyl]-4H-thieno[3,2-b]azepin-6(R)-yl]-3-methylbutanam ide; PA1 8. 3-Amino-3-methyl-N-[6,7,8,9-tetrahydro-8-oxo-9-[[2'-[[[(methylamino)carbon yl]amino]methyl][1,1'-biphenyl]-4-yl]methyl]-5H-pyrido[2,3-b]azepin-7(R)-yl ]butanamide; PA1 9. N-[1,4,5,6,7,8-Hexahydro-5-oxo-4-[[2'-(1H-tetrazol-5-yl)-[1,1'-biphenyl]-4 -yl]methyl]pyrrolo[3,2-b]azepin-6(R)-yl]-3-amino-3-methylbutanamide; PA1 10. N-Ethyl-4'-[[6(R)-[[3-amino-3-methyl-1-oxobutyl]amino]-1,4,5,6,7,8-hexahyd ro-5-oxo-pyrrolo[3,2-b]azepin-4-yl]-methyl][1,1'-biphenyl]-2-carboxamide; PA1 11. N-[1,4,5,6,7,8-Hexahydro-5-oxo-4-[[2'-[[(methylamino)-carbonyl]amino][1,1' -biphenyl]-4-yl]methyl]pyrrolo[3,2-b]-azepin-6(R)-yl]-3-amino-3-methylbutan amide; PA1 12. N-[1,4,5,6,7,8-Hexahydro-5-oxo-4-[[2'-[[[(methylamino)-carbonyl]amino]meth yl][1,1'-biphenyl]-4-yl]methyl]-pyrrolo[3,2-b]azepin-6(R)-yl]-3-amino-3-met hylbutanamide; PA1 13. 3-[2(R)-Hydroxypropyl]amino-3-methyl-N-[6,7,8,9-tetrahydro-8-oxo-9-[[2'-(1 H-tetrazol-5-yl)[1,1'-biphenyl]-4-yl]-methyl]-5H-pyrido[2,3-b]azepin-7(R)-y l]butanamide; PA1 14. N-Ethyl-4'-[[7(R)-[[3-[2(R)-hydroxypropyl]amino-3-methyl-1-oxobutyl]amino] -6,7,8,9-tetrahydro-8-oxo-5H-pyrido[2,3-b]azepin-9-yl]methyl][1,1'-biphenyl ]-2-carboxamide; PA1 15. 3 -[2(R)-Hydroxypropyl]amino-3-methyl-N-[6,7,8,9-tetrahydro-8-oxo-9-[[2'-[[( methylamino)carbonyl]amino][1,1'-biphenyl]-4-yl]methyl]-5H-pyrido[2,3-b]aze pin-7(R)-yl]-butanamide; PA1 16. 3-[2(R)-Hydroxypropyl]amino-3-methyl-N-[6,7,8,9-tetrahydro-8-oxo-9-[[2'-[[ [(methylamino)carbonyl]amino]-methyl][1,1'-biphenyl]-4-yl]methyl]-5H-pyrido [2,3-b]-azepin-7(R)-yl]butanamide; PA1 17. 3-[2(R)-Hydroxypropyl]amino-N-[5,6,7,8-tetrahydro-5-oxo-4-[[2'-(1H-tetrazo l-5-yl)[1,1'-biphenyl]-4-yl]methyl]-4H-thieno[3,2-b]azepin-6(R)-yl]-3-methy lbutanamide PA1 18. N-Ethyl-4'-[[6(R)-[[3-[2(R)-hydroxypropyl]amino-3-methyl-1-oxobutyl]amino] -5,6,7,8-tetrahydro-5-oxo-4H-thieno[3,2-b]azepin-4-yl]methyl][1,1'-biphenyl ]-2-carboxamide; PA1 19. 3-[2(R)-Hydroxypropyl]amino-N-[5,6,7,8-tetrahydro-5-oxo-4-[[2'-[[(methylam ino)carbonyl]amino][1,1'-biphenyl]-4-yl]methyl]-4H-thieno[3,2-b]azepin-6(R )-yl]-3-methylbutanamide; PA1 21. N-[1,4,5,6,7,8-Hexahydro-5-oxo-4-[[2'-(1H-tetrazol-5-yl)-[1,1'-biphenyl]-4 -yl]methyl]pyrrolo[3,2-b]azepin-6(R)-yl]-3-[2(R)-hydroxypropyl]amino-3-meth ylbutanamide; PA1 22. N-Ethyl-4'-[[6(R)-[[3-[2(R)-hydroxypropyl]amino-3-methyl-1-oxobutyl]amino] -1,4,5,6,7,8-hexahydro-5-oxo-pyrrolo[3,2-b]azepin-4-yl]methyl][1,1'-bipheny l]-2-carboxamide; PA1 23. N-[1,4,5,6,7,8-Hexahydro-5-oxo-4-[[2'-[[(methylamino)-carbonyl]amino][1,1' -biphenyl]-4-yl]methyl]pyrrolo[3,2-b]-azepin-6(R )-yl]-3-[2(R)-hydroxypropyl]amino-3-methylbutanamide; PA1 24. N-[1,4,5,6,7,8-Hexahydro-5-oxo-4-[[2'-[[[(methylamino)-carbonyl]amino]meth yl][1,1'-biphenyl]-4-yl]methyl]-pyrrolo[3,2-b]azepin-6(R)-yl]-3-[2(R)-hydro xypropyl]-amino-3-methylbutanamide; PA1 25. 3-[2(S),3-Dihydroxypropyl]amino-3-methyl-N-[6,7,8,9-tetrahydro-8-oxo-9-[[2 '-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4-yl]methyl]-5H-pyrido[2,3-b]azepin-7(R )-yl]butanamide; PA1 26. N-Ethyl-4'-[[7(R)-[[3-[2(S),3-dihydroxypropyl]amino-3-methyl-1-oxobutyl]am ino]-6,7,8,9-tetrahydro-8-oxo-5H-pyrido[2,3-b]azepin-9-yl]methyl][1,1'-biph enyl]-2-carboxamide; PA1 27. 3-[2(S),3-Dihydroxypropyl]amino-3-methyl-N-[6,7,8,9-tetrahydro-8-oxo-9-[[2 '-[[(methylamino)carbonyl]amino]-[1,1'-biphenyl]-4-yl]methyl]-5H-pyrido[2,3 -b]azepin-7(R)-yl]butanamide; PA1 28. 3-[2(S),3-Dihydroxypropyl]amino-3-methyl-N-[6,7,8,9-tetrahydro-8-oxo-9-[[2 '-[[[(methylamino)carbonyl]amino]-methyl][1,1'-biphenyl]-4-yl]methyl]-5H-py rido[2,3-b]-azepin-7(R)-yl]butanamide; PA1 29. 3-[2(S),3-Dihydroxypropyl]amino-N-[5,6,7,8-tetrahydro-5-oxo-4-[[2'-(1H-tet razol-5-yl)[1,1'-biphenyl]-4-yl]methyl]-4H-thieno[3,2-b]azepin-6(R)-yl]-3-m ethylbutanamide PA1 30. N-Ethyl-4'-[[6(R)-[[3-[2(S),3-dihydroxypropyl]amino-3-methyl-1-oxobutyl]am ino]-5,6,7,8-tetrahydro-5-oxo-4H-thieno[3,2-b]azepin-4-yl]methyl][1,1'-biph enyl]-2-carboxamide; PA1 31. 3-[2(S),3-Dihydroxypropyl]amino-N-[5,6,7,8-tetrahydro-5-oxo-4-[[2'-[[(meth ylamino)carbonyl]amino][1,1'-biphenyl]-4-yl]methyl]-4H-thieno[3,2-b]azepin- 6(R)-yl]-3-methylbutanamide; PA1 32. 3-[2(S),3-Dihydroxypropyl]amino-3-methyl-N-[6,7,8,9-tetrahydro-8-oxo-9-[[2 '-[[[(methylamino)carbonyl]amino]-methyl][1,1'-biphenyl]-4-yl]methyl]-5H-py rido[2,3-b]-azepin-7(R)-yl]butanamide; PA1 33. N-[1,4,5,6,7,8-Hexahydro-5-oxo-4-[[2'-(1H-tetrazol-5-yl)-[1,1'-biphenyl]-4 -yl]methyl]pyrrolo[3,2-b]azepin-6(R)-yl]-3-[2(S),3-dihydroxypropyl]amino-3- methylbutanamide; PA1 34. N-Ethyl-4'-[[6(R)-[[3-[2(S),3-dihydroxypropyl]amino-3-methyl-1-oxobutyl]am ino]-1,4,5,6,7,8-hexahydro-5-oxo-pyrrolo[3,2-b]azepin-4-yl]methyl][1,1'-bip henyl]-2-carboxamide; PA1 35. N-[1,4,5,6,7,8-Hexahydro-5-oxo-4-[[2'-[[(methylamino)-carbonyl]amino][1,1' -biphenyl]-4-yl]methyl]pyrrolo[3,2-b]-azepin-6(R)-yl]-3-[2(S),3-dihydroxypr opyl]amino-3-methylbutanamide; PA1 36. N-[1,4,5,6,7,8-Hexahydro-5-oxo-4-[[2'-[[[(methylamino)-carbonyl]amino]meth yl][1,1'-biphenyl]-4-yl]methyl]-pyrrolo[3,2-b]azepin-6(R)-yl]-3-[2(S),3-dih ydroxypropyl]-amino-3-methylbutanamide; PA1 37. 2-Amino-2-methyl-N-[6,7,8,9-tetrahydro-8-oxo-9-[[2'-(1H-tetrazol-5-yl)[1,1 '-biphenyl]-4-yl]methyl]-5H-pyrido[2,3-b]-azepin-7(R)-yl]propanamide; PA1 38. N-Ethyl-4'-[[7(R)-[[2-amino-2-methyl-1-oxopropyl]amino]-6,7,8,9-tetrahydro -8-oxo-5H-pyrido[2,3-b]azepin-9-yl]-methyl][1,1'-biphenyl]-2-carboxamide; PA1 39. 2-Amino-2-methyl-N-[6,7,8,9-tetrahydro-8-oxo-9-[[2'-[[(methylamino)carbony l]amino][1,1'-biphenyl]-4-yl]-methyl]-5H-pyrido[2,3-b]azepin-7(R)-yl]propan amide; PA1 40. 2-Amino-2-methyl-N-[6,7,8,9-tetrahydro-8-oxo-9-[[2'-[[[(methylamino)carbon yl]amino]methyl][1,1'-biphenyl]-4-yl]methyl]-5H-pyrido[2,3-b]azepin-7(R)-yl ]propanamide; PA1 41. 2-Amino-N-[5,6,7,8-tetrahydro-5-oxo-4-[[2'-(1H-tetrazol-5-yl)[1,1'-bipheny l]-4-yl]methyl]-4H-thieno[3,2-b]azepin-6(R)-yl]-2-methylpropanamide PA1 42. N-Ethyl-4'-[[6(R)-[[2-amino-2-methyl-1-oxopropyl]amino]-5,6,7,8-tetrahydro -5-oxo-4H-thieno[3,2-b]azepin-4-yl-]methyl][1,1'-biphenyl]-2-carboxamide; PA1 43. 2-Amino-N-[5,6,7,8-tetrahydro-5-oxo-4-[[2'-[[(methylamino)carbonyl]amino][ 1,1'-biphenyl]-4-yl]methyl]-4H-thieno[3,2-b]azepin-6(R)-yl]-2-methylpropana mide; PA1 44. 2-Amino-2-methyl-N-[6,7,8,9-tetrahydro-8-oxo-9-[[2'-[[[(methylamino)carbon yl]amino]methyl][1,1'-biphenyl]-4-yl]methyl]-5H-pyrido[2,3-b]azepin-7(R)-yl ]propanamide; PA1 45. N-[1,4,5,6,7,8-Hexahydro-5-oxo-4-[[2'-(1H-tetrazol-5-yl)-[1,1'-biphenyl]-4 -yl]methyl]pyrrolo[3,2-b]azepin-6(R)-yl]-2-amino-2-methylpropanamide; PA1 46. N-Ethyl-4'-[[6(R)-[[2-amino-2-methyl-1-oxopropyl]amino]-1,4,5,6,7,8-hexahy dro-5-oxo-pyrrolo[3,2-b]azepin-4-yl]-methyl][1,1'-biphenyl]-2-carboxamide; PA1 47. N-[1,4,5,6,7,8-Hexahydro-5-oxo-4-[[2'-[[(methylamino)-carbonyl]amino][1,1' -biphenyl]-4-yl]methyl]pyrrolo[3,2-b]-azepin-6(R)-yl]-2-amino-2-methylpropa namide and PA1 48. N-[1,4,5,6,7,8-Hexahydro-5-oxo-4-[[2'-[[[(methylamino)-carbonyl]amino]meth yl][1,1'-biphenyl]-4-yl]methyl]-pyrrolo[3,2-b]azepin-6(R)-yl]-2-amino-2-met hylpropanamide.
A deficiency in growth hormone secretion can result in various medical disorders, such as dwarfism.
Various ways are known to release growth hormone. For example, chemicals such as arginine, L-3,4-dihydroxyphenylalanine (L-DOPA), glucagon, vasopressin, and insulin induced hypoglycemia, as well as activities such as sleep and exercise, indirectly cause growth hormone to be released from the pituitary by acting in some fashion on the hypothalamus perhaps either to decrease somatostatin secretion or to increase the secretion of the known secretagogue growth hormone releasing factor (GRF) or an unknown endogenous growth hormone-releasing hormone or all of these.
In cases where increased levels of growth hormone were desired, the problem was generally solved by providing exogenous growth hormone or by administering an agent which stimulated growth hormone production and/or release. In either case the peptidyl nature of the compound necessitated that it be administered by injection. Initially the source of growth hormone was the extraction of the pituitary glands of cadavers. This resulted in a very expensive product and carried with it the risk that a disease associated with the source of the pituitary gland could be transmitted to the recipient of the growth hormone. Recently, recombinant growth hormone has become available which, while no longer carrying any risk of disease transmission, is still a very expensive product which must be given by injection or by a nasal spray.
Other compounds have been developed which stimulate the release of endogenous growth hormone such as analogous peptidyl compounds related to GRF or the peptides of U.S. Pat. No. 4,411,890. These peptides, while considerably smaller than growth hormones are still susceptible to various proteases. As with most peptides, their potential for oral bioavailability is low. The instant compounds are non-peptidyl agents for promoting the release of growth hormone which may be administered parenterally, nasally or by the oral route.